{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:13:17Z","timestamp":1791825197021,"version":"4.3.4"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,12,15]],"date-time":"2024-12-15T00:00:00Z","timestamp":1734220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Durvalumab plus tremelimumab (Dur\/Tre) is a first\u2010line systemic treatment option for unresectable hepatocellular carcinoma (uHCC). However, the management of severe immune\u2010mediated adverse events (imAEs) is challenging. Therefore, we investigated the relationship between severe imAEs and antitumor responses in patients with uHCC treated with Dur\/Tre.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We included 157 patients with uHCC treated with Dur\/Tre in this multicenter, retrospective study and analyzed the relationship between progression\u2010free survival (PFS)\/antitumor response and severe imAEs requiring high\u2010dose corticosteroid treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty\u2010two patients (20.4%) developed severe imAEs, including enterocolitis\/diarrhea (<jats:italic>n<\/jats:italic>\u00a0=\u00a010), liver injury (<jats:italic>n<\/jats:italic>\u00a0=\u00a09), interstitial lung disease (<jats:italic>n<\/jats:italic>\u00a0=\u00a05), rashes (<jats:italic>n<\/jats:italic>\u00a0=\u00a04), cytokine\u2010release syndrome\/fever (<jats:italic>n<\/jats:italic>\u00a0=\u00a02), pancreatitis (<jats:italic>n<\/jats:italic>\u00a0=\u00a02), and others (<jats:italic>n<\/jats:italic>\u00a0=\u00a04) (median follow\u2010up period, 6.8\u00a0months). Infliximab was administered in six patients with steroid\u2010refractory enterocolitis. Although the objective response rate (ORR) and disease control rate (DCR) were significantly higher with first\u2010line therapy than with later\u2010line therapy (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.026), the frequency of severe imAEs was not significantly different (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.221). The ORR and DCR in patients with and without severe imAEs were 15.6% and 17.6% and 65.6% and 47.2%, respectively, with no significant differences. Five patients with severe imAEs, including rashes and liver injury, showed objective responses (partial response\u00a0+\u00a0complete response). Among patients who achieved an objective response, the PFS at 10\u00a0months was good (100% and 70.3% with and without high\u2010dose corticosteroids, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Severe imAEs of Dur\/Tre treatment requiring high\u2010dose corticosteroid treatment did not affect antitumor efficacy, which differed depending on the type of imAEs. Therefore, appropriately managing imAEs is essential to guide sequential treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hepr.14151","type":"journal-article","created":{"date-parts":[[2024,12,15]],"date-time":"2024-12-15T15:09:04Z","timestamp":1734275344000},"page":"577-587","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antitumor effects and immune\u2010mediated adverse events of durvalumab plus tremelimumab treatment for unresectable hepatocellular carcinoma"],"prefix":"10.1111","volume":"55","author":[{"given":"Takanori","family":"Ito","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Nagoya University Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-8386","authenticated-orcid":false,"given":"Shigeo","family":"Shimose","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Kurume University School of Medicine  Kurume Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8801-2505","authenticated-orcid":false,"given":"Joji","family":"Tani","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Department of Gastroenterology and Neurology Kagawa University  Takamatsu Kagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8484-9866","authenticated-orcid":false,"given":"Tetsu","family":"Tomonari","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Oncology Institute of Biomedical Sciences Tokushima University Graduate School of Medicine  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5885-5042","authenticated-orcid":false,"given":"Issei","family":"Saeki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Yamaguchi University Graduate School of Medicine  Yamaguchi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuto","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama University Hospital  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3656-285X","authenticated-orcid":false,"given":"Takeshi","family":"Hatanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Gunma Saiseikai Maebashi Hospital  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyo","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Kawasaki Medical School  Kurashiki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1508-584X","authenticated-orcid":false,"given":"Satoru","family":"Kakizaki","sequence":"additional","affiliation":[{"name":"Department of Clinical Research NHO Takasaki General Medical Center  Takasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kanayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Gunma Saiseikai Maebashi Hospital  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehito","family":"Naito","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Toyohashi Municipal Hospital  Toyohashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamiko","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Anjo Kosei Hospital  Anjo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Yasunaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Fukuyama City Hospital  Fukuyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology National Hospital Organization Fukuyama Medical Center  Fukuyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5688-1335","authenticated-orcid":false,"given":"Hideki","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Kurume University School of Medicine  Kurume Japan"},{"name":"Department of Gastroenterology and Hepatology Iwamoto Internal Medical Clinic  Kitakyusyu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Itano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Kurume Central Hospital  Kurume Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomotake","family":"Shirono","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Kurume University School of Medicine  Kurume Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norikazu","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Division of Laboratory Yamaguchi University Hospital  Ube Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9904-1894","authenticated-orcid":false,"given":"Takafumi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Nagoya University Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0663-0102","authenticated-orcid":false,"given":"Atsushi","family":"Naganuma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology NHO Takasaki General Medical Center  Takasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohji","family":"Nishina","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Kawasaki Medical School  Kurashiki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoyuki","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama University Hospital  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6689-4989","authenticated-orcid":false,"given":"Taro","family":"Takami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Yamaguchi University Graduate School of Medicine  Yamaguchi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuji","family":"Takayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Oncology Institute of Biomedical Sciences Tokushima University Graduate School of Medicine  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7064-4325","authenticated-orcid":false,"given":"Takumi","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Kurume University School of Medicine  Kurume Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Nagoya University Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Hepatology InVestigator Experts in Japan (HIVE\u2010J) Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,15]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"GLOBOCAN2020.https:\/\/gco.iarc.fr\/. Accessed 9 May 2024."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.08.021"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.18"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000466"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1915745"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.11.018"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/evidoa2100070"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.02745"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmra1703481"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010019\u20100218\u20100"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.5012"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102020\u2010000779"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.40695"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.7711"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000479984"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.57.9151"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.01440"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.10.001"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2012.244"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000535839"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010020\u201001549\u20102"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(24)00278\u2010x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535\u2010020\u201001677\u20109"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.16038"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v27.i41.7190"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/07357907.2021.1994586"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523\u2010020\u201000738\u20106"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2024.14530"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.14043"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2023.7013"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12072\u2010021\u201010238\u2010y"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.14078"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.2217\/imt\u20102020\u20100179"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol31080315"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0311084"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637\u2010024\u201001470\u2010y"}],"container-title":["Hepatology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hepr.14151","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T19:02:00Z","timestamp":1743793320000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hepr.14151"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,15]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1111\/hepr.14151"],"URL":"https:\/\/doi.org\/10.1111\/hepr.14151","archive":["Portico"],"relation":{},"ISSN":["1386-6346","1872-034X"],"issn-type":[{"value":"1386-6346","type":"print"},{"value":"1872-034X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,15]]},"assertion":[{"value":"2024-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}